Disruption of the alveolar−endothelial barrier caused by inflammation leads to the progression of septic acute lung injury (ALI). In the present study, we investigated the beneficial effects of simvastatin on the endotoxin lipopolysaccharide (LPS)-induced ALI and its related mechanisms. A model of ALI was induced within experimental sepsis developed by intraperitoneal injection of a single non-lethal LPS dose after short-term simvastatin pretreatment (10−40 mg/kg orally). The severity of the lung tissue inflammatory injury was expressed as pulmonary damage scores (PDS). Alveolar epithelial cell apoptosis was confirmed by TUNEL assay (DNA fragmentation) and expressed as an apoptotic index (AI), and immunohistochemically for cleaved caspase-3, cytochrome C, and anti-apoptotic Bcl-xL, an inhibitor of apoptosis, survivin, and transcriptional factor, NF-kB/p65. Severe inflammatory injury of pulmonary parenchyma (PDS 3.33 ± 0.48) was developed after the LPS challenge, whereas simvastatin significantly and dose-dependently protected lung histology after LPS (p < 0.01). Simvastatin in a dose of 40 mg/kg showed the most significant effects in amelioration alveolar epithelial cells apoptosis, demonstrating this as a marked decrease of AI (p < 0.01 vs. LPS), cytochrome C, and cleaved caspase-3 expression. Furthermore, simvastatin significantly enhanced the expression of Bcl-xL and survivin. Finally, the expression of survivin and its regulator NF-kB/p65 in the alveolar epithelium was in strong positive correlation across the groups. Simvastatin could play a protective role against LPS-induced ALI and apoptosis of the alveolar−endothelial barrier. Taken together, these effects were seemingly mediated by inhibition of caspase 3 and cytochrome C, a finding that might be associated with the up-regulation of cell-survival survivin/NF-kB/p65 pathway and Bcl-xL.

• Klíčová slova
• NF-kB/p65, alveolar epithelial cells, apoptosis, simvastatin, survivin,
• MeSH
• akutní poškození plic * chemicky indukované   farmakoterapie   metabolismus   MeSH
• apoptóza MeSH
• cytochromy c metabolismus   MeSH
• endotoxiny škodlivé účinky   MeSH
• kaspasa 3 genetika   metabolismus   MeSH
• lidé MeSH
• lipopolysacharidy toxicita   MeSH
• NF-kappa B * metabolismus   MeSH
• plíce patologie   MeSH
• pneumocyty metabolismus   MeSH
• simvastatin škodlivé účinky   MeSH
• survivin genetika   MeSH
• upregulace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cytochromy c MeSH
• endotoxiny MeSH
• kaspasa 3 MeSH
• lipopolysacharidy MeSH
• NF-kappa B * MeSH
• simvastatin MeSH
• survivin MeSH

Increasing evidence suggests that apoptosis of tubular cells and renal inflammation mainly determine the outcome of sepsis-associated acute kidney injury (AKI). The study aim was to investigate the molecular mechanism involved in the renoprotective effects of simvastatin in endotoxin (lipopolysaccharide, LSP)-induced AKI. A sepsis model was established by intraperitoneal injection of a single non-lethal LPS dose after short-term simvastatin pretreatment. The severity of the inflammatory injury was expressed as renal damage scores (RDS). Apoptosis of tubular cells was detected by Terminal deoxynucleotidyl transferase-mediated dUTP Nick End Labeling (TUNEL assay) (apoptotic DNA fragmentation, expressed as an apoptotic index, AI) and immunohistochemical staining for cleaved caspase-3, cytochrome C, and anti-apoptotic Bcl-xL and survivin. We found that endotoxin induced severe renal inflammatory injury (RDS = 3.58 ± 0.50), whereas simvastatin dose-dependently prevented structural changes induced by LPS. Furthermore, simvastatin 40 mg/kg most profoundly attenuated tubular apoptosis, determined as a decrease of cytochrome C, caspase-3 expression, and AIs (p < 0.01 vs. LPS). Conversely, simvastatin induced a significant increase of Bcl-XL and survivin, both in the strong inverse correlations with cleaved caspase-3 and cytochrome C. Our study indicates that simvastatin has cytoprotective effects against LPS-induced tubular apoptosis, seemingly mediated by upregulation of cell-survival molecules, such as Bcl-XL and survivin, and inhibition of the mitochondrial cytochrome C and downstream caspase-3 activation.

• Klíčová slova
• Bcl-XL, cytochrome C, endotoxin, simvastatin, survivin, tubular apoptosis,
• MeSH
• akutní poškození ledvin chemicky indukované   farmakoterapie   genetika   patologie   MeSH
• apoptóza účinky léků   MeSH
• cytochromy c genetika   MeSH
• endotoxiny toxicita   MeSH
• epitelové buňky účinky léků   patologie   MeSH
• krysa rodu Rattus MeSH
• ledvinové kanálky účinky léků   patologie   MeSH
• ledviny účinky léků   zranění   metabolismus   patologie   MeSH
• lidé MeSH
• lipopolysacharidy toxicita   MeSH
• protein bcl-X genetika   MeSH
• simvastatin farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• zánět chemicky indukované   farmakoterapie   genetika   patologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cytochromy c MeSH
• endotoxiny MeSH
• lipopolysacharidy MeSH
• protein bcl-X MeSH
• simvastatin MeSH

Endotoxemia is associated by dysregulated apoptosis of immune and non-immune cells. We investigated whether simvastatin has anti-apoptotic effects, and induces hepatocytes and lymphocytes survival signaling in endotoxin-induced liver and spleen injuries. Wistar rats were divided into the groups pretreated with simvastatin (20 or 40 mg/kg, orally) prior to a non-lethal dose of lipopolysaccharide (LPS), the LPS group, and the control. The severity of tissue inflammatory injuries was expressed as hepatic damage scores (HDS) and spleen damage scores (SDS), respectively. The apoptotic cell was detected by TUNEL (Terminal deoxynucleotidyl transferase dUTP Nick End Labeling) and immunohistochemical staining (expression of cleaved caspase-3, and anti-apoptotic Bcl-xL, survivin and NF-κB/p65). Simvastatin dose-dependently abolished HDS and SDS induced by LPS (p < 0.01), respectively. Simvastatin 40 mg/kg significantly decreased apoptotic index and caspase-3 cleavage in hepatocytes and lymphocytes (p < 0.01 vs. LPS group, respectively), while Bcl-XL markedly increased accordingly with simvastatin doses. In the simvastatin, groups were determined markedly increased cytoplasmic expression of survivin associated with nuclear positivity of NF-κB, in both hepatocytes and lymphocytes (p < 0.01 vs. LPS group). Cell-protective effects of simvastatin against LPS seemed to be mediated by up-regulation of survivin, which leads to reduced caspase-3 activation and inhibition of hepatocytes and lymphocytes apoptosis.

• Klíčová slova
• NF-κB/p65, apoptosis, endotoxin, hepatocytes, lymphocytes, simvastatin, survivin,
• Publikační typ
• časopisecké články MeSH

This study is aimed to investigate whether simvastatin induces cardiomyocytes survival signaling in endotoxin (lipopolysaccharide, LSP)-induced myocardial injury, and if so, further to determine a role of survivin in simvastatin-anti-apoptotic effect. Wistar rats were pretreated with simvastatin (10-40 mg/kg po) before a single non-lethal dose of LPS. In myocardial tissue, LPS induced structural disorganization of myofibrils with significant inflammatory infiltrate (cardiac damage score, CDS = 3.87 ± 0.51, p < 0.05), whereas simvastatin dose-dependently abolished structural changes induced by LPS (p < 0.01). Simvastatin in 20 mg/kg and 40 mg/kg pretreatment, dose dependently, attenuated myocardial apoptosis determined as apoptotic index (28.8 ± 4.5% and 18.9 ± 3.5, p < 0.05), decreased cleaved caspase-3 expression (32.1 ± 5.8%, p < 0.01), along with significant Bcl-xL expression in the simvastatin groups (p < 0.01). Interestingly, in the simvastatin groups were determined significantly increased expression of survivin (p < 0.01), but in negative correlation with cleaved caspase-3 and apoptotic indices (p < 0.01). Simvastatin has a cardioprotective effects against LPS induced apoptosis. The effect may be mediated by up-regulation of survivin via activation of NF-κB, which leads to reduced activation of caspase-3 and consequent apoptosis of cardiomyocytes in experimental sepsis.

• MeSH
• aplikace orální MeSH
• apoptóza účinky léků   MeSH
• Escherichia coli MeSH
• kardiomyocyty účinky léků   patologie   MeSH
• kardiomyopatie etiologie   patologie   prevence a kontrola   MeSH
• kaspasa 3 metabolismus   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• lipopolysacharidy toxicita   MeSH
• modely nemocí na zvířatech MeSH
• myokard cytologie   patologie   MeSH
• potkani Wistar MeSH
• sepse komplikace   etiologie   MeSH
• signální transdukce účinky léků   MeSH
• simvastatin aplikace a dávkování   MeSH
• srdce účinky léků   MeSH
• statiny aplikace a dávkování   MeSH
• survivin metabolismus   MeSH
• transkripční faktor RelA metabolismus   MeSH
• upregulace účinky léků   MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Birc5 protein, rat MeSH Prohlížeč
• Casp3 protein, rat MeSH Prohlížeč
• kaspasa 3 MeSH
• lipopolysacharidy MeSH
• Rela protein, rat MeSH Prohlížeč
• simvastatin MeSH
• statiny MeSH
• survivin MeSH
• transkripční faktor RelA MeSH